CN114478332B - Synthesis method of alkyl trifluoromethyl sulfide - Google Patents
Synthesis method of alkyl trifluoromethyl sulfide Download PDFInfo
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Abstract
The invention discloses a synthesis method of alkyl trifluoromethyl sulfide, belonging to the field of organic chemistry. The invention takes aryl or alkyl sulfonyl chloride and trifluoromethyl trimethylsilane as raw materials, and obtains alkyl trifluoromethyl thioether through iodide catalysis in the presence of a reducing agent and alkali. The method can be used for reaction at room temperature, the raw materials are widely and easily available, the reaction yield is up to 81%, and a novel way for indirect trifluoromethylthio is provided in the field of organofluorine chemistry. The obtained product has wide application in the fields of medicine, pesticide, petrochemical industry and the like.
Description
Technical Field
The invention particularly relates to a synthesis method of alkyl trifluoromethyl sulfide, belonging to the field of organic chemistry.
Background
Organic fluorine-containing compounds are a very important substance and are widely applied to modern production and living. It is reported that about 20% of medicines and 35% of pesticides have been commercialized at present, containing at least 1 fluorine atom. Due to the nature of fluorine atoms themselves, such as fluorine atoms having a strong electronegativity and a small atomic radius, a more stable C-F bond is formed relative to C-H bonds. Wherein the trifluoromethylthio group (SCF) 3 ) Because of the high fat solubility and the strong electron withdrawing capability, the organic compound containing the trifluoromethylthio is mainly applied to the medical field of people, and the introduction of the trifluoromethylthio into the medicine can obviously improve the stability, fat solubility, biological activity and the like of the metabolism.
The methods for constructing aryl trifluoromethyl sulfide are reported at present mainly as follows: fluorohalogenexchange of halogen-containing precursors, electrophilic, nucleophilic and radical trifluoromethylation of sulfur-containing substrates, and direct trifluoromethylthio using various trifluoromethylthio reagents. These methods have the problems of harsh reaction conditions, excessive metal catalysis, expensive reagents, unfriendly environment and the like. Therefore, the development of a method for introducing trifluoromethyl thio in a low-cost, efficient and green way has very important practical application value.
Disclosure of Invention
According to the invention, aryl or alkyl sulfonyl chloride and trifluoromethyl trimethylsilane are selected to react under the catalysis of iodine to obtain the alkyl trifluoromethyl thioether. Compared with the existing synthesis method, the method has the characteristics of wide substrate adaptability, mild reaction conditions, low-cost and easily-obtained reagents and the like.
The invention aims to provide a method for synthesizing a hydrocarbon trifluoromethyl thioether compound, which comprises the steps of taking sulfonyl chloride compounds shown in a formula 1 and trifluoromethyl trimethylsilane shown in a formula 2 as reactants in an organic solvent, reacting under the action of a catalyst, a reducing agent and alkali, and obtaining the hydrocarbon trifluoromethyl thioether compound shown in a formula 3 after the reaction is finished:
wherein R is selected from C 1 -C 18 Alkyl, halogenated C 1 -C 18 Alkyl, C 1 -C 18 Alkoxy, aryl.
In one embodiment of the invention, R is preferably C 1 -C 4 Alkyl, aryl.
In one embodiment of the invention, aryl is a substituted or unsubstituted benzene ring, naphthalene ring; substitution includes one to three substitutions; the substituted groups being selected from halogen, C 1 -C 8 Alkyl, phenyl.
In one embodiment of the present invention, the organic solvent includes any one or more of acetonitrile, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide.
In one embodiment of the invention, the temperature of the reaction is from 25 ℃ to 100 ℃. Preferably 25 ℃.
In one embodiment of the invention, the reaction time is 10 to 20 hours; specifically, the time is selected to be 14h.
In one embodiment of the invention, the molar feed ratio of the sulfonyl chloride compound to the trifluoromethyl trimethylsilane is 1 (2-4).
In one embodiment of the invention, the catalyst is any one or more of potassium iodide, sodium iodide, tetrabutylammonium iodide and iodine.
In one embodiment of the present invention, the catalyst is used in an amount of 0.1 to 1 equivalent (molar equivalent) to the sulfonyl chloride-based compound. Specifically, 0.2-0.4equiv is selected.
In one embodiment of the invention, the reducing agent is any one or more of triphenylphosphine, diphenylphosphine, and tricyclohexylphosphine.
In one embodiment of the present invention, the reducing agent is used in an amount of 1.0 to 2.0 equivalents (molar equivalents) to the sulfonyl chloride-based compound. Specifically 1.5 equivalents are optional.
In one embodiment of the present invention, the base includes any one or more of cesium carbonate, cesium fluoride, potassium t-butoxide, sodium acetate, potassium carbonate, potassium fluoride.
In one embodiment of the present invention, the base is used in an amount of 2.0 to 4.0 equivalents (molar equivalents) to the sulfonyl chloride-based compound.
In one embodiment of the invention, a novel green economical synthesis method comprises the following steps:
aryl or alkyl sulfonyl chloride and trifluoromethyl trimethylsilane are used as raw materials, and are stirred and reacted for a period of time at 25-120 ℃ to obtain a crude product of the alkyl trifluoromethyl thioether compound, and then the crude product is filtered, washed, decompressed distilled and separated by column chromatography to obtain the pure alkyl trifluoromethyl thioether compound.
In the method, the main separation method adopts a rapid column chromatography method to obtain the final product of the hydrocarbyl trifluoromethyl sulfide compound.
In one embodiment of the invention, the method is preferably carried out as follows: adding aryl or alkyl sulfonyl chloride, trifluoromethyl trimethylsilane, triphenylphosphine, cesium fluoride and potassium iodide into a reaction tube containing N, N-dimethylformamide according to the molar ratio of 1:4:1.5:4:0.2, stirring for 8-24 hours at 25-120 ℃, and separating and purifying to obtain a target product.
The beneficial effects are that:
the invention provides a novel synthesis method of trifluoromethyl aryl sulfide compound.
The process of the invention is carried out under nitrogen (N) 2 ) In the atmosphere, aryl or alkyl sulfonyl chloride is used as a substrate, trifluoromethyl trimethylsilane is used as a trifluoromethyl reagent, and the trifluoromethyl sulfation of the sulfonyl chloride can be realized in one step under the action of a catalyst, a reducing agent and alkali, so that the target alkyl trifluoromethyl thioether compound is obtained.
The method adopts the cheap and easily available trifluoromethyl trimethylsilane as a trifluoromethyl reagent, uses iodide as a catalyst, and has the advantages of environment friendliness, mild reaction conditions, simple operation and low economic cost; in addition, the method can obtain the target product with good yield only by reacting for 14 hours, and the reaction is fast and efficient.
The synthesis method of the invention converts the simple and easily obtained aryl or alkyl sulfonyl chloride into the hydrocarbon trifluoromethyl thioether compound which has wide application in the fields of medicine, pesticide, petrochemical industry and the like under a simpler condition.
Drawings
FIG. 1 is a synthetic route diagram of the method of the present invention.
Detailed Description
The following are specific embodiments of the present invention.
The synthetic route diagram of the embodiment of the invention is shown in fig. 1:
aryl or alkyl sulfonyl chloride and trifluoromethyl trimethylsilane are used as raw materials, potassium iodide is used as a catalyst, triphenylphosphine is used as a reducing agent, cesium fluoride is used as alkali, N, N-dimethylformamide is used as a solvent, and the raw materials are fully reacted in an oil bath at 25-100 ℃ for 14 hours in a reaction tube. The reaction expression is shown in figure 1.
Example 1: synthesis of 4-tert-butylphenyl trifluoromethyl sulfide
To a 25mL reaction tube equipped with a stirrer were added 4-tert-butylbenzenesulfonyl chloride (116 mg,0.5 mmol), trifluoromethyl trimethylsilane (284 mg,2.0 mmol), triphenylphosphine (196 mg,0.75 mmol), cesium fluoride (304 mg,2.0 mmol), potassium iodide (16.6 mg,0.1 mmol) and N, N-dimethylformamide (3.0 mL), respectively, and the mixture was reacted sufficiently at 25℃for 14 hours. After the completion of the reaction, cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution, respectively, the solvent was removed by vacuum concentration, and the target product was purified by column chromatography to give 78mg of the product in 67% yield (nuclear magnetic resonance yield: 81%).
1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝8.4Hz,2H),7.47–7.39(m,2H),1.36(s,9H). 19 F NMR(376MHz,CDCl 3 )δ-42.99(s,3F). 13 C NMR(101MHz,CDCl 3 )δ154.4(s),136.2(s),129.7(q,J＝307.9Hz),126.6(s),120.9(dd,J＝4.1,2.0Hz),34.9(s),31.1(s).
Example 2: synthesis of 4-biphenyltrifluoro methyl sulfide
To a 25mL reaction tube equipped with a stirrer were added 4-biphenylsulfonyl chloride (136 mg,0.5 mmol), trifluoromethyl trimethylsilane (284 mg,2.0 mmol), triphenylphosphine (196 mg,0.75 mmol), cesium fluoride (304 mg,2.0 mmol), potassium iodide (16.6 mg,0.1 mmol) and N, N-dimethylformamide (3.0 mL), respectively, and the mixture was reacted sufficiently at 25℃for 14 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with distilled water and saturated sodium chloride solution, and concentrated in vacuo to remove the solvent, and the target product was purified by column chromatography to give 92mg of the product in 73% yield.
1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝8.3Hz,2H),7.64–7.55(m,4H),7.50–7.42(m, 2H),7.41–7.35(m,1H). 19 F NMR(376MHz,CDCl 3 )δ-42.70(s). 13 C NMR(101MHz,CDCl 3 )δ 143.8(s),139.7(s),136.7(s),129.6(q,J＝308.3Hz),129.0(s),128.2(s),127.2(s),123.1(dd,J＝ 3.9,1.9Hz).
Example 3: synthesis of 4-methoxyphenyl trifluoromethyl sulfide
To a 25mL reaction tube equipped with a stirrer were added 4-methoxybenzenesulfonyl chloride (104 mg,0.5 mmol), trifluoromethyltrimethylsilane (284 mg,2.0 mmol), triphenylphosphine (196 mg,0.75 mmol), cesium fluoride (304 mg,2.0 mmol), potassium iodide (16.6 mg,0.1 mmol) and N, N-dimethylformamide (3.0 mL), respectively, and the mixture was reacted sufficiently at 25℃for 14 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, washed with distilled water and saturated sodium chloride solution, respectively, and the solvent was removed by vacuum concentration, and the target product was purified by column chromatography to give 39mg of a product with a yield of 37%.
1 H NMR(400MHz,CDCl 3 )δ7.57(d,J＝8.8Hz,2H),6.99–6.87(m,2H),3.83(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-43.94(s). 13 C NMR(101MHz,CDCl 3 )δ161.9(s),138.3(s),129.6(q, J＝308.1Hz),115.0(s),114.8(d,J＝2.2Hz),55.4(s).
EXAMPLE 4 Synthesis of 4-biphenyltrifluoromethyl sulfide with different bases
Referring to example 2, the corresponding aryltrifluoromethyl sulfide was synthesized by replacing the base with cesium fluoride, potassium phosphate, potassium fluoride, cesium carbonate, respectively, under the same conditions.
Specific yield a The results are shown in Table 1.
TABLE 1 influence of different bases on the synthesis of 4-biphenyltrifluormethyl sulfide a
a. The yield was fluorine spectrum yield.
The result shows that: the cesium fluoride of example 2 was replaced with potassium fluoride, cesium carbonate, potassium t-butoxide, sodium acetate as a base to obtain a product with a yield not exceeding 67% worse than that of example 2.
EXAMPLE 5 Synthesis of 4-biphenyltrifluoromethyl sulfide with different solvents
Referring to example 2, the corresponding aryltrifluoromethyl sulfide was synthesized by substituting cesium fluoride with a base and substituting acetonitrile, N-dimethylacetamide, dimethyl sulfoxide, and water with a solvent from N, N-dimethylformamide, respectively, under the same conditions.
Specific yield a The results are shown in Table 2.
TABLE 2 influence of different solvents on the Synthesis of 4-biphenyltrifluoromethyl sulfide a
| Solvent(s) | Yield (%) |
| CH 3 CN | 22 |
| |
3 |
| DMF | 70 |
| DMAc | 16 |
| H 2 O | 0 |
a. The yield was fluorine spectrum yield.
The result shows that: acetonitrile, N-dimethylacetamide, dimethyl sulfoxide and water are adopted to replace N, N-dimethylformamide in the example 2 as solvents, and the yields are not more than 22 percent.
EXAMPLE 6 Synthesis of 4-biphenyltrifluoromethyl sulfide at different reaction temperatures
Referring to example 2, the corresponding aryltrifluoromethyl sulfide was synthesized by replacing the reaction temperature with 25℃at 60℃at 90℃at 120℃under the same conditions as the reaction temperature of 100 ℃.
Specific yield results are shown in Table 3.
TABLE 3 influence of different reaction temperatures on the synthesis of 4-biphenyltrifluormethyl sulfide a
| Temperature (. Degree. C.) | Yield (%) |
| 25 | 81 |
| 60 | 68 |
| 90 | 76 |
| 120 | 60 |
The a yield is the fluorine spectrum yield.
The result shows that: the yield was significantly reduced by replacing 25℃in example 2 with 60℃at 90℃at 120 ℃.
EXAMPLE 7 Synthesis of 4-biphenyltrifluoromethyl sulfide with different iodine catalysts
Referring to example 2, the thioether product was prepared by replacing the iodine-containing catalyst with sodium iodide, ammonium iodide, tetraethylammonium iodide, iodine, respectively, from potassium iodide, and the others were unchanged. The specific results are shown in Table 4.
TABLE 4 influence of different iodine-containing catalysts on the Synthesis of 4-biphenyltrifluormethyl sulfide a
| Iodine-containing catalysis | Yield (%) |
| Without adding | 0 |
| Potassium iodide | 81 |
| Sodium iodide | 75 |
| Tetrabutylammonium iodide | 46 |
| Iodine | 32 |
The a yield is the fluorine spectrum yield.
Claims (7)
1. A method for synthesizing a hydrocarbon trifluoromethyl thioether compound is characterized in that in an organic solvent, a sulfonyl chloride compound shown in a formula 1 and trifluoromethyl trimethylsilane shown in a formula 2 are used as reactants, and the hydrocarbon trifluoromethyl thioether compound shown in a formula 3 is obtained after the reaction is finished by reacting under the action of a catalyst, a reducing agent and alkali:
wherein R is selected from C 1 -C 18 Alkyl, halogenated C 1 -C 18 Alkyl, substituted or unsubstituted benzene ring, naphthalene ring; substitution includes one to three substitutions; the substituted groups being selected from halogen, C 1 -C 8 Alkyl, phenyl;
the catalyst is one or more of potassium iodide and sodium iodide;
the organic solvent is N, N-dimethylformamide;
the alkali is one or more of cesium carbonate, cesium fluoride, sodium acetate, potassium carbonate and potassium fluoride;
the reducing agent is any one or more of triphenylphosphine, diphenylphosphine and tricyclohexylphosphine.
2. The method of claim 1, wherein R is selected from C 1 -C 4 Alkyl, substituted or unsubstituted benzene ring, naphthalene ring; substitution includes one to three substitutions; the substituted groups being selected from halogen, C 1 -C 8 Alkyl, phenyl.
3. The method of claim 1, wherein the temperature of the reaction is from 25 ℃ to 100 ℃.
4. The method according to claim 1, wherein the molar ratio of sulfonyl chloride compound to trifluoromethyl trimethylsilane is 1 (2-4).
5. The method according to claim 1, wherein the molar ratio of sulfonyl chloride compound to catalyst is 1: (0.1-1).
6. The method according to claim 1, wherein the molar ratio of sulfonyl chloride compound to base is 1: (2.0-4.0).
7. The method according to any one of claims 1 to 6, wherein the molar ratio of sulfonyl chloride compound to reducing agent is 1: (1.0-2.0).
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